Viral diseases are caused by a combination of virus-mediated cytopathic effects and an acutely overactive (cytokine storm) or chronic inflammatory response. The immune response, intended to control the infection, frequently exacerbates the disease and causes complications, such as blindness (viral stromal keratitis), encephalitis (West Nile virus infections), acute respiratory distress syndrome (pandemic influenza) and even death. Effective anti-viral drugs in general do not prevent inflammatory complications and therefore, corticosteroids are frequently required. However, steroids can exacerbate viral replication resulting in a difficult to interrupt vicious cycle where viral replication and inflammation cannot be controlled at the same time and in the end result in severe damage of the tissues. Accordingly, there is need for improved therapies that may be able to control viral replication and inflammation simultaneously and therefore prevent damage to the tissues.
Improved therapies to control viral replication and information have potential application in severe viral infections of the eye. The cornea is the highly transparent outer-most layer of the eye that provides a large portion of the eye's refractive power and shields against infection by pathogens. Since even the smallest of cells can affect visual acuity, normal corneal tissue lacks all vasculature and is immunologically privileged to reduce influx of inflammatory cells. Generally, in the absence of ocular disease and/or trauma, the lack of vasculature and inflammatory response of the cornea ensures visual acuity is maintained. However, under certain ocular situations, the lack of vascularization and/or suppressed inflammatory response may be compromised.
For example, trauma to the eye by a foreign object (e.g. dust, sand, or mechanical), a surgical procedure (e.g. refractive surgery or transplantation), or infection of the cornea with viruses, bacteria, or other infectious agents, may initiate an inflammatory reaction mediated by the immune response and neovascularization (formation of new blood vessels). These processes may result in destructive cytopathic causes and may lead to thickening and opacification (clouding) of the cornea, which may ultimately lead to a reduction of visual clarity and sometimes sight.
Trauma of the cornea (e.g., surgical or accidental) may lead to pain, inflammation, scarring, neovascularization, and/or discharge. Even in the absence of a particular infectious agent, corneal lesions can affect visual acuity and progress to further damage to the eye. Generally, corneal trauma may be typically treated with strong corticosteroids which may decrease inflammation. However, these agents may have severe secondary effects, including: 1) increased risk of infections (common in ocular trauma) by diminishing the protective immune response; 2) delayed healing of the cornea; 3) loss of an intact epithelial barrier; 4) increased ocular pressure; and 5) eventual deterioration of vision.
Globally, infection- and inflammation-associated eye diseases are the leading causes of corneal blindness and visual morbidity, with over 500 million individuals affected. Pathogen-associated ocular diseases are a complex combination of pathogen-mediated trauma and host-mediated pathologies, often with the most severe sequelae being a consequence of host inflammatory responses. Corneal infections are often treated with a combination of antimicrobials to eliminate pathogens and corticosteroids to reduce inflammation. However, several problems may arise from this approach.
First, effective antimicrobials are not always available for the infectious agents of the eye. For example, Adenoviral infections, which may cause epidemic outbreaks of highly contagious keratoconjunctivitis (pink eye) that can last up to a month, are not readily treatable by antimicrobials. Second, even when anti-viral medications are available and can kill the viruses, they cannot control the inflammatory response triggered by the infection. Typically, inflammation accounts for the clinical presentation of an ocular disease. Often the inflammatory response may cause secondary but more severe damage of the cornea. Third, many pathogens evolve drug resistance, which enables the pathogen to replicate even in the presence of the antimicrobial. For example, some strains of herpes simplex viruses (HSV), which are the leading cause of infectious corneal blindness in the United States, and Chlamydia trachomatis, a leading cause of infectious blindness worldwide, have developed drug resistant strains. Fourth, co-administration of steroids to suppress host anti-pathogen immune responses (inflammation) in infected individuals also blocks the protective role of the immune responses and enables uncontrolled replication, as well as pathogen-mediated disease progression.
Four herpes viruses are linked to severe infections of the eye that can result in blindness: HSV-1, HSV-2, VZV, and CMV. The National Eye Institute estimates that 450,000 Americans have experienced some form of ocular herpetic disease, with 50,000 new and recurrent cases diagnosed annually. Despite effective antivirals against HSV, approximately 25% of these cases develop serious inflammation-associated stromal keratitis. Individuals that have experienced ocular herpes have a 50% chance of recurrence with each repeated episode triggering deleterious CD4 and CD8 T cell responses that can result in scarring of the cornea and an eventual need for corneal transplantation. Although corneal transplantation restores the patient's sight, it does not cure the patient of his or her lifelong herpetic infection; therefore, recrudescence of infection in these individuals may renew the vicious cycle and result in damage to the implanted cornea.
Herpetic stromal keratitis (HSK), a blinding eye disease associated with HSV-1 infection, is not simply a virus-mediated disease of the corneal stroma, but a virus-associated chronic immuno-inflammatory disease of the eye. It is mediated by many complex immune mechanisms including macrophages, dendritic cells, T cells (Th1, Th2, T-regs and Th17), antibodies and even cytokines. Therefore, even with anti-herpetic drugs controlling HSV-1 replication, the vision threatening disease progresses through immune-mediated pathologies.
Clinical presentations of ocular diseases are a complex combination of trauma and host-mediated inflammation-associated pathologies that must be simultaneously controlled and resolved to prevent development of vision-threatening sequelae. Currently, no treatments exist that can effectively remedy all of these issues within the eye.